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IC50 for resistant cell lines as compared to IC50 of parental cell line

Periodontal disease is more common in individuals with rheumatoid arthritis (RA) who have detectable anti-citrullinated protein antibodies (ACPAs), implicating oral mucosal inflammation in RA pathogenesis. Here, we performed paired analysis of human and bacterial transcriptomics in longitudinal blood samples from RA patients. We found that patients with RA and periodontal disease experienced repeated oral bacteremias associated with transcriptional signatures of ISG15 + HLADR hi and CD48 high S100A2 pos monocytes, recently identified in inflamed RA synovia and blood of those with RA flares. The oral bacteria observed transiently in blood were broadly citrullinated in the mouth, and their in situ citrullinated epitopes were targeted by extensively somatically hypermutated ACPAs encoded by RA blood plasmablasts. Together, these results suggest that (i) periodontal disease results in repeated breaches of the oral mucosa that release citrullinated oral bacteria into circulation, which (ii) activate inflammatory monocyte subsets that are observed in inflamed RA synovia and blood of RA patients with flares and (iii) activate ACPA B cells, thereby promoting affinity maturation and epitope spreading to citrullinated human antigens.

The tumor microenvironment (TME) enhances regulatory T (T

The immune mechanisms that mediate synovitis and joint destruction in rheumatoid arthritis (RA) remain poorly defined. Although increased levels of CD8+T cells have been described in RA, their role in pathogenesis remains unclear. Here we perform single cell transcriptome and T cell receptor (TCR) sequencing of CD8+T cells derived from anti-citrullinated protein antibodies (ACPA)+ RA blood. We identifyGZMB+CD8+subpopulations containing large clonal lineage expansions that express cytotoxic and tissue homing transcriptional programs, while aGZMK+CD8+memory subpopulation comprises of smaller clonal expansions that express effector T cell transcriptional programs. We demonstrate RA citrullinated autoantigens presented by MHC class I activate RA blood-derivedGZMB+CD8+T cells to expand, express cytotoxic mediators, and mediate killing of target cells. We also demonstrate that these clonally expandedGZMB+CD8+cells are present in RA synovium. These findings suggest that cytotoxic CD8+T cells targeting citrullinated antigens have a role in contributing to synovitis and joint tissue destruction in ACPA+ RA.

Objective Data-informed decision making is valued among school districts, but challenges remain for local health departments to provide data, especially during a pandemic. We describe the rapid planning and deployment of a school-based COVID-19 surveillance system in a metropolitan US county. Methods In 2020, we used several data sources to construct disease- and school-based indicators for COVID-19 surveillance in Franklin County, an urban county in central Ohio. We collected, processed, analyzed, and visualized data in the COVID-19 Analytics and Targeted Surveillance System for Schools (CATS). CATS included web-based applications (public and secure versions), automated alerts, and weekly reports for the general public and decision makers, including school administrators, school boards, and local health departments. Results We deployed a pilot version of CATS in less than 2 months (August–September 2020) and added 21 school districts in central Ohio (15 in Franklin County and 6 outside the county) into CATS during the subsequent months. Public-facing web-based applications provided parents and students with local information for data-informed decision making. We created an algorithm to enable local health departments to precisely identify school districts and school buildings at high risk of an outbreak and active SARS-CoV-2 transmission in school settings. Practice Implications Piloting a surveillance system with diverse school districts helps scale up to other districts. Leveraging past relationships and identifying emerging partner needs were critical to rapid and sustainable collaboration. Valuing diverse skill sets is key to rapid deployment of proactive and innovative public health practices during a global pandemic.

Background: Thrombocytopenia is a common hematological abnormality observed in neonatal sepsis and considered as early, nonspecific marker of sepsis. The studies related to organism specific platelet response are few. Objective: To assess the prevalence of thrombocytopenia and to study changes in various platelet parameters in relation to different isolated organism. Methods: A prospective observational study involving neonates with 1st episode of culture positive sepsis was done over a period of 18 months. The platelet parameters studied were incidence, degree, duration of thrombocytopenia; mean platelet volume and platelet nadir among neonate with specific organism isolated. Results: Out of 114 culture positive sepsis 31% Klebsiella, 30% Pseudomonas, 13% Citrobacter, 18% CONS, 4% Staphylococcus Aureus (S Aureus) and 3% had Acinetobacter sepsis. Overall prevalence of thrombocytopenia was 88%, of which klebsiella and S. Aureus sepsis observed 100% prevalence of thrombocytopenia followed by 88% pseudomonas, 80% coagulase negative staphylococci (CONS), 75% Acinetobacter and 66% Citrobacter sepsis. The proportion of severe degree of thrombocytopenia (18% Vs 4%), higher MPV (61% Vs 54%) and longer duration of thrombocytopenia (3.63 ± 0.49 Vs 2.95 ± 0.52) was observed more with Gram negative sepsis than with Gram positive sepsis and statistically significant difference in platelet nadir was observed with Gram negative sepsis. Severe degree of thrombocytopenia was seen in 50% neonates with Acinetobacter and 23% with Klebsiella sepsis. Acinetobacter, Klebsiella and Pseudomonas sepsis had higher mean MPV value, longer duration of thrombocytopenia and lowest platelet nadir. The platelet parameters were less affected with Gram positive organism. Conclusion: Thrombocytopenia is a frequent occurrence in neonates with sepsis especially with Gram negative organism. Sepsis with Acinetobacter, Klebsiella & Pseudomonas organism was associated with prolonged duration, higher MPV and lower platelet count as compared to other isolated organisms.

Multiple sclerosis (MS) is a neuroinflammatory demyelinating disease of the central nervous system (CNS) with a high socioeconomic relevance. The pathophysiology of MS, which is both complex and incompletely understood, is believed to be influenced by various environmental determinants, including diet. Since the 1990s, a correlation between the consumption of bovine milk products and MS prevalence has been debated. Here, we show that C57BL/6 mice immunized with bovine casein developed severe spinal cord pathology, in particular, demyelination, which was associated with the deposition of immunoglobulin G. Furthermore, we observed binding of serum from casein-immunized mice to mouse oligodendrocytes in CNS tissue sections and in culture where casein-specific antibodies induced complement-dependent pathology. We subsequently identified myelin-associated glycoprotein (MAG) as a cross-reactive antigenic target. The results obtained from the mouse model were complemented by clinical data showing that serum samples from patients with MS contained significantly higher B cell and antibody reactivity to bovine casein than those from patients with other neurologic diseases. This reactivity correlated with the B cell response to a mixture of CNS antigens and could again be attributed to MAG reactivity. While we acknowledge disease heterogeneity among individuals with MS, we believe that consumption of cow’s milk in a subset of patients with MS who have experienced a previous loss of tolerance to bovine casein may aggravate the disease. Our data suggest that patients with antibodies to bovine casein might benefit from restricting dairy products from their diet.

We present an investigation of the microstructure and rheological behavior of catalyst inks consisting of Fe-N-C platinum group metal-free catalysts and a perfluorosulfonic acid ionomer in a dispersion medium (DM) of water and 1-propanol (

Neuroblastomas (NBs) have heterogeneous clinical behavior, from spontaneous regression or differentiation to relentless progression. Evidence from our laboratory and others suggests that neurotrophin receptors contribute to these disparate behaviors. Previously, the role of TRK receptors in NB pathogenesis was investigated. In the present study, the expression of RET and its co‑receptors in a panel of NB cell lines was investigated and responses to cognate ligands GDNF, NRTN, and ARTN with GFRα1‑3 co‑receptor expression, respectively were found to be correlated. RET expression was high in NBLS, moderate in SY5Y, low/absent in NBEBc1 and NLF cells. All cell lines expressed at least one of GFRα co‑receptors. In addition, NBLS, SY5Y, NBEBc1 and NLF cells showed different morphological changes in response to ligands. As expected, activation of RET/GFRα3 by ARTN resulted in RET phosphorylation. Interestingly, activation of TrkA by its cognate ligand NGF resulted in RET phosphorylation at Y905, Y1015, and Y1062, and this was inhibited in a dose‑dependent manner by the TRK inhibitor (CEP‑701). Conversely, RET activation by ARTN in NBLS cells led to phosphorylation of TrkA. This suggests a physical association between RET and TRK proteins, and cross‑talk between these two receptor pathways. Finally, RET, GFR and TRK expression in primary tumors was investigated and a significant association between RET, its co‑receptors and TRK expression was demonstrated. Thus, the present data support a complex model of interacting neurotrophin receptor pathways in the regulation of cell growth and differentiation in NBs.

Background: Birth asphyxia can lead to hypoxic damage to liver at cellular level which leads to release of liver enzymes in blood as well as altered liver function. This study aimed to study the alteration of hepatic function in birth asphyxia and correlate it with different stages of hypoxic ischemic encephalopathy (HIE).Method: A case control study was conducted at SMIMER Surat which involved 115 cases and 115 controls. Cases were full term neonates admitted in the NICU with an APGAR score of 6 or less at 1 minute of birth while controls were those neonates with an APGAR score of 7 or more. Blood samples were taken at 72 hours of life and liver function tests of the 2 groups were compared.Results: The difference in aspartate transferase (AST), alanine transferase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP) levels of the cases and controls were statistically significant (p0.5).Conclusions: The present study showed that the serum levels of hepatic enzymes were higher in full term neonates with perinatal asphyxia than full term neonates without perinatal asphyxia at the age of 72 hours. The enzyme levels showed an increasing trend with increasing severity of HIE.

Neuroblastoma (NB) is one of the most common and deadly childhood solid tumors. These tumors are characterized by clinical heterogeneity, from spontaneous regression to relentless progression, and the Trk family of neurotrophin receptors plays an important role in this heterogeneous behavior. We wanted to determine if entrectinib (RXDX-101, Ignyta, Inc.), an oral Pan-Trk, Alk and Ros1 inhibitor, was effective in our NB model. In vitro effects of entrectinib, either as a single agent or in combination with the chemotherapeutic agents Irinotecan (Irino) and Temozolomide (TMZ), were studied on an SH-SY5Y cell line stably transfected with TrkB. In vivo growth inhibition activity was studied in NB xenografts, again as a single agent or in combination with Irino-TMZ. Entrectinib significantly inhibited the growth of TrkB-expressing NB cells in vitro, and it significantly enhanced the growth inhibition of Irino-TMZ when used in combination. Single agent therapy resulted in significant tumor growth inhibition in animals treated with entrectinib compared to control animals [p < 0.0001 for event-free survival (EFS)]. Addition of entrectinib to Irino-TMZ also significantly improved the EFS of animals compared to vehicle or Irino-TMZ treated animals [p < 0.0001 for combination vs. control, p = 0.0012 for combination vs. Irino-TMZ]. We show that entrectinib inhibits growth of TrkB expressing NB cells in vitro and in vivo, and that it enhances the efficacy of conventional chemotherapy in in vivo models. Our data suggest that entrectinib is a potent Trk inhibitor and should be tested in clinical trials for NBs and other Trk-expressing tumors.

The microstructure of platinum-group-metal-free (PGM-free) catalyst layers is known significantly impact mass and proton transport and is critical for optimization of PGM-free fuel cells.1 It is known that catalyst ink formulation can influence interactions between catalyst and ionomer which in turn influence the catalyst layer microstructure. In this talk, we present an investigation of catalyst inks consisting of Fe-N-C catalysts and Nafion ionomer to understand how the ratio of H2O and 1-propanol (nPA) influences ink microstructure. Steady-shear and dynamic-oscillatory-shear rheology, in combination with x-ray scattering, were used to study the interparticle interactions and the agglomerated structure of the inks. In the absence of ionomer, the inks were significantly agglomerated, approaching a gel-like microstructure. Increasing H2O% was found to increase agglomeration due to hydrophobic nature of the catalysts. Addition of ionomer was found to initially stabilize catalysts against agglomeration for all H2O%. However, at high ionomer concentrations (I/C > 0.35) interesting differences were observed based on H2O%. The nPA-rich inks were found to remain predominantly stable while ionomer appears to flocculate H2O-rich inks. Finally, the ink microstructure is compared with catalyst layer microstructure, which shows a direct correlation. This work shows that the controlling the ink microstructure is critical to designing optimized catalyst layers. This work was authored by the National Renewable Energy Laboratory, operated by Alliance for Sustainable Energy, LLC, for the U.S. Department of Energy (DOE) under Contract No. DE-AC36-08GO28308. The submitted manuscript was created, in part, by UChicago Argonne, LLC, Operator of Argonne National Laboratory, Argonne, U.S. Department of Energy Office of Science laboratory, operated under Contract No. DE-AC02- 06CH11357. This research used the resources of the Advanced Photon Source (APS), a U.S. Department of Energy (DOE) Office of Science User Facility, operated for the DOE Office of Science by Argonne National Laboratory, also under Contract No. DE-AC02-06CH11357. Funding provided as part of the Electrocatalyst Consortium (ElectroCAT), an Energy Materials Network Consortium funded by the U.S. Department of Energy, Office of Energy Efficiency and Renewable Energy, Hydrogen and Fuel Cell Technologies Office. The views expressed in the article do not necessarily represent the views of the DOE or the U.S. Government. The U.S. Government retains and the publisher, by accepting the article for publication, acknowledges that the U.S. Government retains a nonexclusive, paid-up, irrevocable, worldwide license to publish or reproduce the published form of this work, or allow others to do so, for U.S. Government purposes. (1) Wang, G.; Osmieri, L.; Star, A. G.; Pfeilsticker, J.; Neyerlin, K. C. Elucidating the Role of Ionomer in the Performance of Platinum Group Metal-Free Catalyst Layer via in Situ Electrochemical Diagnostics. Journal of The Electrochemical Society 2020, 167 (4), 044519. https://doi.org/10.1149/1945-7111/ab7aa1.

A better understanding of processes controlling the development and function of pancreatic islets is critical for diabetes prevention and treatment. Here, we reveal a previously unappreciated function for pancreatic β2-adrenergic receptors (Adrb2) in controlling glucose homeostasis by restricting islet vascular growth during development. Pancreas-specific deletion of Adrb2 results in glucose intolerance and impaired insulin secretion in mice, and unexpectedly, specifically in females. The metabolic phenotypes were recapitulated by Adrb2 deletion from neonatal, but not adult, β-cells. Mechanistically, Adrb2 loss increases production of Vascular Endothelial Growth Factor-A (VEGF-A) in female neonatal β-cells and results in hyper-vascularized islets during development, which in turn, disrupts insulin production and exocytosis. Neonatal correction of islet hyper-vascularization, via VEGF-A receptor blockade, fully rescues functional deficits in glucose homeostasis in adult mutant mice. These findings uncover a regulatory pathway that functions in a sex-specific manner to control glucose metabolism by restraining excessive vascular growth during islet development.

TrkB with its ligand, brain-derived neurotrophic factor (BDNF), are overexpressed in the majority of high-risk neuroblastomas (NB). Entrectinib is a novel pan-TRK, ALK, and ROS1 inhibitor that has shown excellent preclinical efficacy in NB xenograft models, and recently it has entered phase 1 trials in pediatric relapsed/refractory solid tumors. We examined entrectinib-resistant NB cell lines to identify mechanisms of resistance. Entrectinib-resistant cell lines were established from five NB xenografts initially sensitive to entrectinib therapy. Clonal cell lines were established in increasing concentrations of entrectinib and had >10X increase in IC50. Cell lines underwent genomic and proteomic analysis using whole-exome sequencing, RNA-Seq, and proteomic expression profiling with confirmatory RT-PCR and Western blot analysis. There was no evidence of NTRK2 (TrkB) gene mutation in any resistant cell lines. Inhibition of TrkB was maintained in all cell lines at increasing concentrations of entrectinib (target independent). PTEN pathway downregulation and ERK/MAPK pathway upregulation were demonstrated in all resistant cell lines. One of these clones also had increased IGF1R signaling, and two additional clones had increased P75 expression, which likely increased TrkB sensitivity to ligand. In conclusion, NB lines overexpressing TrkB developed resistance to entrectinib by multiple mechanisms, including activation of ERK/MAPK and downregulation of PTEN signaling. Individual cell lines also had IGF1R activation and increased P75 expression, allowing preservation of downstream TrkB signaling in the presence of entrectinib. An understanding of changes in patterns of expression can be used to inform multimodal therapy planning in using entrectinib in phase II/III trial planning.

Introduction Increased development and use of next-generation sequencing in clinical diagnostics has revolutionized precision medicine. Steps prior to a specimen arriving at a diagnostic facility, including pathological evaluation, are crucial parameters determining specimen quality and success of comprehensive genomic profiling (CGP). This observational study identified factors that may influence tissue acquisition for commercial CGP in clinical oncology. Methods Data were collected from deidentified patients (n = 63) from select US pathology labs enrolled in a Foundation Medicine (FMI) early access program for the CGP test FoundationOne CDx (Foundation Medicine). A representative substudy cohort (n = 20) with qualitative information available was selected. Lab visit frequency by FMI was monitored for 42 cases. Tissue acquisition turnaround time (TA-TAT) was separated into stages: (1) tissue request to pathology lab acknowledgment, (2) pathology lab acknowledgment to tissue pathology review, (3) tissue pathology review to packaging, and (4) packaging to tissue arriving at FMI. Results Median TA-TAT for the total population was 5.0 days (range, 0-27.0) and 3.5 days for the substudy cohort (range, 1.0-11.0). The duration of each TA-TAT stage was evaluated separately and varied between labs (0%-71.4% of total TA-TAT). TA-TAT was longer for unstained slides compared with formalin-fixed, paraffin-embedded (FFPE) tissue blocks. There was a trend for decreased TA-TAT when stages 1 and 2 occurred on the same day versus different days. For the cases with lab-visit frequency reported, those with biweekly visits had shorter TA-TAT (biweekly: n = 12, median = 2.0, 2.5th-97.5th percentile range, 0.3-5.7 days; single visit: n = 30, median = 5.5, 2.5th-97.5th percentile range, 0.7-13.1 days). Conclusions Understanding and optimizing the tissue acquisition workflow may reduce TA-TAT, thereby facilitating report delivery and subsequent treatment guidance to patients. Funding Bristol-Myers Squibb. Professional medical writing and editorial assistance was provided by Katerina Pipili, PhD, and Jay Rathi, MA, of Spark Medica Inc, funded by Bristol-Myers Squibb.

Nanomedicine-based strategies have the potential to improve therapeutic performance of a wide range of anticancer agents. However, the successful implementation of nanoparticulate delivery systems requires the development of adequately sized nanocarriers delivering their therapeutic cargo to the target in a protected, pharmacologically active form. The present studies focused on a novel nanocarrier-based formulation strategy for SN-38, a topoisomerase I inhibitor with proven anticancer potential, whose clinical application is compromised by toxicity, poor stability and incompatibility with conventional delivery vehicles. SN-38 encapsulated in biodegradable sub-100 nm sized nanoparticles (NP) in the form of its rapidly activatable prodrug derivative with tocopherol succinate potently inhibited the growth of neuroblastoma cells in a dose- and exposure time-dependent manner, exhibiting a delayed response pattern distinct from that of free SN-38. In a xenograft model of neuroblastoma, prodrug-loaded NP caused rapid regression of established large tumors, significantly delayed tumor regrowth after treatment cessation and markedly extended animal survival. The NP formulation strategy enabled by a reversible chemical modification of the drug molecule offers a viable means for SN-38 delivery achieving sustained intratumoral drug levels and contributing to the potency and extended duration of antitumor activity, both prerequisites for effective treatment of neuroblastoma and other cancers.

Background Chromodomain-helicase DNA binding protein 5 (CHD5) is an important tumor suppressor gene deleted from 1p36.31 in neuroblastomas (NBs). High CHD5 expression is associated with a favorable prognosis, but deletion or low expression is frequent in high-risk tumors. We explored the role of CHD5 expression in the neuronal differentiation of NB cell lines. Methods NB cell lines SH-SY5Y (SY5Y), NGP, SK-N-DZ, IMR5, LAN5, SK-N-FI, NB69 and SH-EP were treated with 1–10 μM 13-cis-retinoic acid (13cRA) for 3–12 days. qRT-PCR and Western blot analyses were performed to measure mRNA and protein expression levels, respectively. Morphological differences were examined by both phase contrast and immunofluorescence studies. Results Treatment of SY5Y cells with 13cRA caused upregulation of CHD5 expression in a time- and dose-dependent manner (1, 5, or 10 μM for 7 or 12 days) and also induced neuronal differentiation. Furthermore, both NGP and SK-N-DZ cells showed CHD5 upregulation and neuronal differentiation after 13cRA treatment. In contrast, 13cRA treatment of IMR5, LAN5, or SK-N-FI induced neither CHD5 expression nor neuronal differentiation. NB69 cells showed two different morphologies (neuronal and substrate adherent) after 12 days treatment with 10 μM of 13cRA. CHD5 expression was high in the neuronal cells, but low/absent in the flat, substrate adherent cells. Finally, NGF treatment caused upregulation of CHD5 expression and neuronal differentiation in SY5Y cells transfected to express TrkA (SY5Y-TrkA) but not in TrkA-null parental SY5Y cells, and both changes were blocked by a pan-TRK inhibitor. Conclusions Treatment with 13cRA induces neuronal differentiation only in NB cells that upregulate CHD5. In addition, NGF induced CHD5 upregulation and neuronal differentiation only in TrkA expressing cells. Together, these results suggest that CHD5 is downstream of TrkA, and CHD5 expression may be crucial for neuronal differentiation induced by either 13cRA or TrkA/NGF signaling. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0425-y) contains supplementary material, which is available to authorized users.

Immunotherapy represents an extremely promising treatment approach for cancer patients. The success in this field has been signified by multiple recent approvals of checkpoint inhibitors across a range of cancer types. Subsequently, there is an increasing need to understand why certain patients and diseases benefit from these treatments while others do not, as well as how to maximize the benefits from these treatments. To address some of these questions, we used an in vivo screening platform, MuScreen, which allows for evaluation of multiple syngeneic models and treatment modalities.We have characterized baseline and treated tumor immune infiltrates for a panel of syngeneic models using flow cytometry. The correlation between responsiveness and effects of checkpoint inhibitors (e.g., anti-PD-1), and macrophage targeted agents (e.g., CSF1R inhibition) on immune infiltrates including tumor-associated macrophages (TAMs) were investigated in 6 syngeneic models. Furthermore, M1/M2 polarization of macrophages was investigated to explore the potential role of these cells in establishing an immunosuppressed tumor microenvironment that may affect response to therapy. Here, we show that the baseline immune cell population varies across models, and that immune checkpoint inhibitors and macrophage-targeted agents had variable efficacy across different tumor models. We also present the correlation of immune cell infiltration, including tumor infiltrating lymphocytes (TILs), TAMs, and responsiveness to immunotherapy intervention. Having an in-depth understanding of the immune make up of a model in which an immunomodulatory compound is screened is paramount for successful translation into the clinic. A well-characterized and fully profiled panel of syngeneic models such as the MuScreen platform allows for finding the right model for screening test compounds to be used alone or in combination with immunotherapy. Citation Format: Yuki Kato Maves, Hooman Izadi, Elvira C. Talaoc, Deborah Yan, Charlene Echegaray, Andrew Calinisan, Krystal Moya, Heather Venant, Mitchell Garland, Radhika Iyer, Shounak Gosh, Stephanie Songco, Jayant Thatte, Tommy Broudy. Comparative study of anti-PD1 and CSF1R inhibition on tumor-infiltrating lymphocytes and macrophage populations across a panel of syngeneic tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2811. doi:10.1158/1538-7445.AM2017-2811

Purpose: Neuroblastoma (NB) is one of the most common and deadly solid tumors of childhood. The Trk family of neurotrophin receptors plays an important role in clinical behavior of NBs. Overexpression of TrkB and its ligand, BDNF, is associated with poor prognosis. We wanted to determine if RXDX-101, an oral pan-TRK, ROS1 and ALK inhibitor, would be effective in our NB xenograft model, either alone or in combination with conventional chemotherapy. Experimental Design: We tested the in vitro effects of RXDX-101 as a single agent, or in combination with the chemotherapeutic agents irinotecan and temozolomide (Irino-TMZ), using a subclone of the SH-SY5Y NB cell line transfected with TrkB. We also examined in vivo growth inhibition of TrkB-expressing NB xenografts with RXDX-101 alone or in combination with Irino-TMZ. Results: RXDX-101 significantly inhibited growth of TrkB-expressing NB cells in vitro. Enhanced in vitro inhibition was observed when RXDX-101 was used in combination with Irino-TMZ. Single agent therapy with RXDX-101 resulted in significant tumor growth inhibition compared to control animals [p Conclusions: We show that RXDX-101 inhibits growth of TrkB expressing NB cells in vitro and in vivo. Furthermore, RXDX-101 cotreatment enhanced the efficacy of conventional chemotherapy in our NB xenograft model. Our data suggest that RXDX-101 has potential for incorporation in clinical trials for NB and other Trk expressing tumors. Citation Format: Radhika Iyer, Rebecca L. Golden, Koumudi Naraparaju, Jamie L. Croucher, Peng Guan, Gang Li, Zachary Hornby, Garrett M. Brodeur. The TRK inhibitor RXDX-101 enhances the efficacy of temozolomide and irinotecan in a xenograft model of neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5390. doi:10.1158/1538-7445.AM2015-5390

Purpose: Neuroblastoma (NB) is the most common and deadly solid tumor in childhood. The majority of NB patients have advanced stage disease and a poor prognosis, so more effective, less toxic therapy is needed. We wanted to determine if more targeted delivery of chemotherapeutic agents would improve efficacy and reduce systemic toxicity. We developed a novel nanocarrier-based strategy for tumor-targeted delivery of a prodrug of SN38, the active metabolite of irinotecan. Experimental Design: We formulated ultrasmall-sized ( Results: All SN38-TS NP regimens were far superior to irinotecan, and “cures” were obtained in all NP arms (no cures with irinotecan). SN38-TS NP delivery resulted in 200x the amount of SN38 in NB tumors at 4 hr post-treatment, and 25% of the 4-hr SN38 level remained at 72 hr post-treatment, compared to no SN38 detected at 24 hr post-treatment for the irinotecan arm; no toxicity was seen with NPs. Conclusions: We conclude that this SN38-TS NP formulation improved delivery, retention, and efficacy, without causing systemic toxicity. Citation Format: Radhika Iyer, Jamie L. Croucher, Michael Chorny, Jennifer L. Mangino, Ivan S. Alferiev, Robert J. Levy, Venkatadri Kolla, Garrett M. Brodeur. Nanoparticle delivery of an SN38 conjugate is more effective than Irinotecan in a mouse model of Neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5537. doi:10.1158/1538-7445.AM2015-5537